In drafting the zone, the border between the two powers shifted, placing colonies of either power on the other side of the border. Both powers offered the colonists the option to resettle on a planet within their own government's area, but most colonists refused. (TNG: "Journey's End")

Unhappy with the decisions of the Federation and threatened by the secretive and illegal shipment of weapons to Cardassian colonists by their government, Federation colonists created a group called the Maquis, their goal to gain independence from the Cardassians. Some factions within the Federation and Starfleet supported the cause, and, like their Cardassian counterparts, provided weapons and other aid. (DS9: "The Maquis, Part I", "The Maquis, Part II"; TNG: "Preemptive Strike")

Between 2370 and 2373, the Maquis movement grew, with hostilities flaring into a war and terrorist campaign against the Cardassians. The Cardassian government responded in kind, but, in 2372, became distracted by the Klingon-Cardassian War. With the Cardassians' attention turned away from them, the Maquis grew more successful, and, by 2373, were ready to declare their colonies independent. (DS9: "For the Cause", "Blaze of Glory")

Many of the Cardassian survivors fled into the Demilitarized Zone, seeking refuge. The Klingons pursued them into the DMZ and forcibly annexed not only Cardassian colonies but also several former Federation worlds controlled by the Maquis.

The Maquis found themselves fighting for their homes, with some even allying with the Cardassian survivors against the common enemy. But the Klingons began an indiscriminate purge, wiping out Cardassians and Maquis alike, along with anyone else who stood in their way.

By 2373, Cardassia and the DMZ were almost entirely under Klingon control. Some surviving Maquis went into hiding in the Badlands, while others carried out terrorist actions against the Klingons, just as they had against the Cardassians. However, the machinations of the Founders operating in the Klingon Empire did more to destabilize the situation than any Maquis strike.

By late 2373, the Great Houses had fallen into a state of feudal conflict, and many outposts in the DMZ were abandoned. The remaining Klingons were more concerned with their conflicts than in actively quashing the Maquis. And so Michael Eddington and Cal Hudson made an overture to Captain Benjamin Sisko - Maquis help in the war effort against Leyton's forces in return for Federation aid in removing the Klingons from the DMZ. Sisko presented the offer to Admiral William Ross, who agreed to the proposal. Eddington and the Maquis entered the Federation Civil War and were instrumental in successfully retaking Earth and ending the conflict in early 2374.

In the aftermath, however, the Federation Council adopted Admiral Nechayev's isolationist policies and backed out of the agreement with Eddington, once again turning their backs on the Maquis worlds.

Hudson and Eddington returned to the DMZ and tried to rally the colonists and Cardassian survivors into an offensive against the Klingons. Their plans were crushed when the House of Duras massacred the colony on Cervalis V, killing 60,000 men, women, and children.

Over the next five years, anarchy reigned in the Demilitarized Zone. Mercenaries and privateers constantly plagued the few functioning colonies, and the Orion Syndicate also took an interest in the area. Certain elements in the Romulan Star Empire also sought to gain control of the DMZ, and Tal Shiar abducted Cardassian and Maquis survivors to serve in covert labor camps.

When the new Federation President sought to reverse the "Nechayev doctrine" that had been in effect since the war, Starfleet made plans to send a vessel into the Demilitarized Zone as an "olive branch" to help restore order to the area. In 2379, the new USS Pendragon was tasked with that mission, under the command of Captain Timothy Sinclair.